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The PI3-kinase isoform p110δ is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner.

  • Jianmin Sun
  • Sofie Mohlin
  • A Lundby
  • Julhash U. Kazi
  • U Hellman
  • Sven Påhlman
  • J V Olsen
  • Lars Rönnstrand
Publishing year: 2014
Language: English
Pages: 5360-5369
Publication/Series: Oncogene
Volume: 33
Issue: 46
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

PI3-kinase has a crucial role in transformation mediated by the oncogenic c-Kit mutant D816V. In this study, we demonstrate that the c-Kit/D816V-mediated cell survival is dependent on an intact direct binding of PI3-kinase to c-Kit. However, mutation of this binding site had little effect on the PI3-kinase activity in the cells, suggesting that c-Kit/D816V-mediated cell survival is dependent on PI3-kinase but not its kinase activity. Furthermore, inhibition of the lipid kinase activity of PI3-kinase led only to a slight inhibition of cell survival. Knockdown of the predominant PI3-kinase isoform p110δ in c-Kit/D816V-expressing Ba/F3 cells led to reduced cell transformation both in vitro and in vivo without affecting the overall PI3-kinase activity. This suggests that p110δ has a lipid-kinase-independent role in c-Kit/D816V-mediated cell transformation. We furthermore demonstrate that p110δ is phosphorylated at residues Y524 and S1039 and that phosphorylation requires an intact binding site for PI3-kinase in c-Kit/D816V. Overexpression of p110δ carrying the Y523F and S1038A mutations significantly reduced c-Kit/D816V-mediated cell survival and proliferation. Taken together, our results demonstrate an important lipid-kinase-independent role of p110δ in c-Kit/D816V-mediated cell transformation. This furthermore suggests that p110δ could be a potential diagnostic factor and selective therapeutic target for c-Kit/D816V-expressing malignancies.Oncogene advance online publication, 11 November 2013; doi:10.1038/onc.2013.479.


  • Cancer and Oncology


  • Molecular Cancer Research
  • ISSN: 1476-5594
Sven Påhlman
E-mail: sven [dot] pahlman [at] med [dot] lu [dot] se


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